Lippincott Williams & Wilkins
SUPPLEMENTAL DIGITAL CONTENTa Phase 2b, Randomized, Placebo-Controlled, Double-Blind, Dose-Ranging Study OF THE NEUROKININ 3 RECEPTOR ANTAGONIST FEZOLINETANT FOR VASOMOTOR SYMPTOMS associated with menopauseGraeme L. Fraser, PhD; Samuel Lederman, MD; Arthur Waldbaum, MD; Robin Kroll, MD; Nanette Santoro, MD; Misun Lee, PhD; Laurence Skillern, MD; Steven Ramael, MDCONTENTSTable S1. Secondary Efficacy Outcomes: Frequency of Moderate/Severe VMS and Severity per 24 Hours in Weeks 1 and 2, Full Analysis SetTable S2. Secondary Efficacy Outcomes: Frequency of Mild/Moderate/Severe VMS and Severity per 24 Hours, Full Analysis SetTable S3. Liver Function Tests, Safety Analysis SetFigure S1. Response Rates and Odds of Response with Fezolinetant Versus Placebo Based on ≥50% Reduction in Frequency of Moderate/Severe VMS at Last On-Treatment Visit, Full Analysis SetFigure S2. Endometrial Thickness, Safety Analysis SetTable S1. Secondary Efficacy Outcomes: Frequency of Moderate/Severe VMS and Severity per 24 Hours in Weeks 1 and 2, Full Analysis SetWkTreatment group (n)Frequency of moderate/severe VMSper 24 hoursaSeverity of moderate/severe VMSper 24 hoursaChange from baselineDifference from placeboChange from baselineDifference from placeboMean (SE)Mean (SE)95% CIP valueMean (SE)Mean (SE)95% CIP value1Placebo (n=42)-2.1 (0.59)———-0.1 (0.10)———Fezolinetant15 mg BID (n=45)-3.8 (0.56)-1.7 (0.78)-3.23, -0.17.0297-0.4 (0.09)-0.3 (0.13)-0.60, -0.08.009830 mg BID (n=43)-5.3 (0.58)-3.1 (0.78)-4.66, -1.58<.0001-0.5 (0.10)-0.4 (0.13)-0.63, -0.11.004860 mg BID (n=43)-5.7 (0.57)-3.6 (0.78)-5.10, -2.02<.0001-0.6 (0.10)-0.5 (0.13)-0.80, -0.28<.000190 mg BID (n=41)-6.4 (0.60)-4.2 (0.79)-5.78, -2.66<.0001-0.8 (0.10)-0.7 (0.13)-1.00, -0.47<.000130 mg QD (n=41)-3.3 (0.60)-1.2 (0.79)-2.76, 0.36.1378-0.1 (0.10)-0.1 (0.13)-0.32, 0.21.676160 mg QD (n=44)-4.7 (0.56)-2.6 (0.78)-4.13, -1.05.0010-0.4 (0.09)-0.3 (0.13)-0.57, -0.05.0188120 mg QD (n=44)-4.7 (0.58)-2.6 (0.78)-4.10, -1.04.0011-0.4 (0.10)-0.4 (0.13)-0.61, -0.10.00672Placebo (n=42)-3.7 (0.60)———-0.2 (0.12)———Fezolinetant15 mg BID (n=44)-5.3 (0.57)-1.6 (0.79)-3.20, -0.07.0405-0.5 (0.12)-0.4 (0.17)-0.68, -0.03.033530 mg BID (n=42)-6.8 (0.59)-3.1 (0.80)-4.70, -1.55.0001-0.7 (0.12)-0.6 (0.17)-0.91, -0.25.000760 mg BID (n=43)-6.8 (0.58)-3.1 (0.80)-4.66, -1.52.0001-1.0 (0.12)-0.8 (0.17)-1.14, -0.48<.000190 mg BID (n=39)-7.3 (0.61)-3.7 (0.81)-5.26, -2.07<.0001-1.2 (0.13)-1.1 (0.17)-1.41, -0.74<.000130 mg QD (n=41)-5.4 (0.61)-1.7 (0.81)-3.34, -0.15.0325-0.3 (0.13)-0.2 (0.17)-0.50, 0.17.322760 mg QD (n=43)-6.0 (0.57)-2.4 (0.80)-3.92, -0.78.0035-0.6 (0.12)-0.4 (0.17)-0.77, -0.11.0085120 mg QD (n=43)-5.7 (0.59)-2.1 (0.79)-3.61, -0.49.0102-0.8 (0.12)-0.6 (0.17)-0.95, -0.30.0002aFrom mixed effect model for repeated measures, with change from baseline as the dependent variable and treatment group, visit, and smoking status as factors and baseline measurement as a covariate, as well as interaction of treatment by week and an interaction of baseline measurement by week.Table S2. Secondary Efficacy Outcomes: Frequency of Mild/Moderate/Severe VMS and Severity per 24 Hours, Full Analysis SetWkTreatment group (n)Frequency of mild/moderate/severe VMSper 24 hoursaSeverity of mild/moderate/severe VMSper 24 hoursaChange from baselineDifference from placeboChange from baselineDifference from placeboMean (SE)Mean (SE)95% CIP valueMean (SE)Mean (SE)95% CIP value4Placebo (n=42)-4.0 (0.63)———-0.3 (0.13)———Fezolinetant15 mg BID (n=40)-5.7 (0.60)-1.7 (0.84)-3.36, -0.06.0428-0.8 (0.12)-0.5 (0.18)-0.85, -0.16.004630 mg BID (n=41)-7.0 (0.62)-3.0 (0.84)-4.65, -1.34.0004-1.0 (0.13)-0.6 (0.18)-0.99, -0.29.000360 mg BID (n=40)-7.2 (0.61)-3.2 (0.84)-4.88, -1.58.0001-1.1 (0.13)-0.8 (0.18)-1.14, -0.45<.000190 mg BID (n=37)-8.1 (0.64)-4.1 (0.85)-5.73, -2.37<.0001-1.4 (0.13)-1.1 (0.18)-1.41, -0.70<.000130 mg QD (n=40)-6.0 (0.64)-2.0 (0.85)-3.64, -0.28.0225-0.8 (0.13) -0.4 (0.18)-0.77, -0.06.020960 mg QD (n=43)-6.8 (0.60)-2.8 (0.84)-4.49, -1.19.0008-0.9 (0.12)-0.6 (0.18)-0.93, -0.24.0011120 mg QD (n=42)-7.1 (0.62)-3.1 (0.84)-4.70, -1.42.0003-1.1 (0.13)-0.7 (0.18)-1.07, -0.38<.000112Placebo (n=37)-5.7 (0.58)———-0.8 (0.15)———Fezolinetant15 mg BID (n=38)-7.1 (0.54)-1.4 (0.76)-2.90, 0.09.0653-1.2 (0.15)-0.4 (0.21)-0.80, 0.02.059630 mg BID (n=37)-7.6 (0.57)-2.0 (0.76)-3.46, -0.47.0102-1.3 (0.15)-0.4 (0.21)-0.85, -0.03.036060 mg BID (n=31)-8.5 (0.57)-2.9 (0.77)-4.38, -1.36.0002-1.6 (0.15)-0.7 (0.21)-1.15, -0.32.000690 mg BID (n=31)-8.8 (0.59)-3.2 (0.78)-4.72, -1.67<.0001-1.6 (0.16)-0.8 (0.21)-1.23, -0.39.000230 mg QD (n=33)-7.4 (0.59)-1.8 (0.78)-3.30, -0.25.0231-1.0 (0.15)-0.2 (0.21)-0.62, 0.21.322760 mg QD (n=36)-8.0 (0.55)-2.4 (0.76)-3.88, -0.87.0021-1.3 (0.15)-0.5 (0.21)-0.89, -0.07.0220120 mg QD (n=36)-8.1 (0.57)-2.5 (0.76)-3.96, -0.97.0013-1.3 (0.15)-0.4 (0.21)-0.84, -0.02.0380aFrom mixed effect model for repeated measures with change from baseline as the dependent variable and treatment group, visit, smoking status as factors and baseline measurement as a covariate, as well as interaction of treatment by week and an interaction of baseline measurement by week.Table S3. Liver Function Tests, Safety Analysis SetParameterPlacebo (n=42)Fezolinetant, n (%)15 mg BID (n=43)30 mg BID (n=41)60 mg BID (n=41)90 mg BID (n=40)30 mg QD (n=41)60 mg QD (n=43)120 mg QD (n=42)AST or ALT, n (%)>3 × ULN001 (2.4)3 (7.3)2 (5.0)01 (2.3)2 (4.8)>5 × ULN0001 (2.4)2 (5.0)01 (2.3)1 (2.4)>8 × ULN0001 (2.4)1 (2.5)01 (2.3)0>10 × ULN0000001 (2.3)0Total bilirubin, n (%)>1.5 × ULN001 (2.4)0001 (2.3)0>2.0 × ULN00000000Alkaline phosphatase >1.5 × ULN, n (%)002 (4.9)1 (2.4)02 (4.9)2 (4.7)0ALT and/or AST >3 × ULN and total bilirubin 2 × ULN, n (%)00000000ALT and/or AST >3 × ULN and ALP <2 × ULN and total bilirubin >2 × ULN, n (%)00000000ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal.Figure S1. Response Rates and Odds of Response with Fezolinetant Versus Placebo Based on ≥50% Reduction in Frequency of Moderate/Severe VMS at Last On-Treatment Visit, Full Analysis SetVMS=vasomotor symptoms.aP<.05 for all pairwise comparisons of fezolinetant vs placebo, with no adjustments for multiplicity.Figure S2. Endometrial Thickness, Safety Analysis Set ................
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